Axl belongs to the TAM subfamily of receptor tyrosine kinases (RTKs) that also includes Tyro3 and Mer. The TAM receptors are characterized by a combination of two immunoglobin-like domains and dual fibronectin type III repeats in the extracellular region and a cytoplasmic kinase domain. The ligands for TAM receptors are Gas6 (growth-arrest-specific 6) and protein S, two vitamin-K dependent proteins that show 43% amino acid sequence identity and share similar domain structures. Each protein has an N-terminal GIa domain containing 11 g-carboxyglutamic acid residues, followed by four epidermal growth factor (EGF)-like modules, and a C-terminal sex hormone-binding globlin (SHBG)-like structure consisting of two tandem laminin G domains. The SHBG domain is both necessary and sufficient for TAM receptor binding and activation, whereas the GIa domain binds the negatively charged membrane phospholipids and plays an important role in TAM-mediated phagocytosis of apoptotic cells. TAM activation and signalling has been implicated in multiple cellular responses including cell survival, proliferation, migration and adhesion.
Dysregulation of Axl or its ligand Gas6 is implicated in the pathogenesis of a variety of human cancers. Overexpression of Axl has been reported in a wide array of human cancers (lung, prostate, breast, gastric, pancreatic, ovarian, thyroid, blood cancers, renal cell carcinoma as well as glioblastoma . . . ) and is associated with invasiveness, metastasis and negative prognosis. These findings suggest that Axl may be involved in the regulation of multiple aspects of tumorigenesis including tumor growth, invasion and angiogenesis and thus represents a target for therapeutic intervention in cancer especially for the development of anti-metastatic cancer therapy and for other multiple cancer treatment including treatment of drug resistance.
Accordingly, anti-Axl monoclonal antibodies have been described for use in the treatment of cancers. For example publications relating to anti-Axl antibodies include WO2009/063965, WO2009/062690, and WO2011/014457.
Other roles of Axl dependent or not of its ligands such as inhibition of immune functions, activation of platelet aggregation and viral infection inducer (as an example, Ebola and Lassa virus uptake is promoted by Axl) highlight the potential of Axl as therapeutic target for other applications than oncology.